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Hum Mol Genet. 2015 Feb 15;24(4):1185-99. doi: 10.1093/hmg/ddu516. Epub 2014 Oct 8.

Genome-wide enrichment analysis between endometriosis and obesity-related traits reveals novel susceptibility loci.

Author information

1
Wellcome Trust Center for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
2
Statistical Genetics.
3
Wellcome Trust Center for Human Genetics, University of Oxford, Oxford OX3 7BN, UK, Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
4
Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA, Unit of Nutritional Epidemiology, Institute for Environmental Medicine, Karolinska Institutet, PO Box 210, SE-171 77 Stockholm, Sweden.
5
Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
6
Wellcome Trust Center for Human Genetics, University of Oxford, Oxford OX3 7BN, UK, Department of Genomics of Common Disease, Imperial College London, London W12 0NN, UK, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LJ, UK.
7
Neurogenetics.
8
Wellcome Trust Center for Human Genetics, University of Oxford, Oxford OX3 7BN, UK, Department of Biostatistics, University of Liverpool, Duncan Building, Daulby Street, Liverpool L69 3GA, UK.
9
Molecular Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4029, Australia.
10
Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.
11
Wellcome Trust Center for Human Genetics, University of Oxford, Oxford OX3 7BN, UK, Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge 02142 MA, USA and.
12
Wellcome Trust Center for Human Genetics, University of Oxford, Oxford OX3 7BN, UK, Nuffield Department of Obstetrics and Gynaecology & Endometriosis CaRe Centre, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK krinaz@well.ox.ac.uk.

Abstract

Endometriosis is a chronic inflammatory condition in women that results in pelvic pain and subfertility, and has been associated with decreased body mass index (BMI). Genetic variants contributing to the heritable component have started to emerge from genome-wide association studies (GWAS), although the majority remain unknown. Unexpectedly, we observed an intergenic locus on 7p15.2 that was genome-wide significantly associated with both endometriosis and fat distribution (waist-to-hip ratio adjusted for BMI; WHRadjBMI) in an independent meta-GWAS of European ancestry individuals. This led us to investigate the potential overlap in genetic variants underlying the aetiology of endometriosis, WHRadjBMI and BMI using GWAS data. Our analyses demonstrated significant enrichment of common variants between fat distribution and endometriosis (P = 3.7 × 10(-3)), which was stronger when we restricted the investigation to more severe (Stage B) cases (P = 4.5 × 10(-4)). However, no genetic enrichment was observed between endometriosis and BMI (P = 0.79). In addition to 7p15.2, we identify four more variants with statistically significant evidence of involvement in both endometriosis and WHRadjBMI (in/near KIFAP3, CAB39L, WNT4, GRB14); two of these, KIFAP3 and CAB39L, are novel associations for both traits. KIFAP3, WNT4 and 7p15.2 are associated with the WNT signalling pathway; formal pathway analysis confirmed a statistically significant (P = 6.41 × 10(-4)) overrepresentation of shared associations in developmental processes/WNT signalling between the two traits. Our results demonstrate an example of potential biological pleiotropy that was hitherto unknown, and represent an opportunity for functional follow-up of loci and further cross-phenotype comparisons to assess how fat distribution and endometriosis pathogenesis research fields can inform each other.

PMID:
25296917
PMCID:
PMC4576730
DOI:
10.1093/hmg/ddu516
[Indexed for MEDLINE]
Free PMC Article

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